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Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by mutant ataxin-3 with an abnormally expanded polyQ tract and is the most common dominantly inherited ataxia worldwide. There are no suitable therapeutic options for this disease. Autophagy, a defense mechanism against the toxic effects of aggregation-prone misfolded proteins, has been shown to have beneficial effects on neurodegenerative diseases. Thus, trehalose, which is an autophagy inducer, may have beneficial effects on SCA3. In the present study, we examined the effects of trehalose on an SCA3 cell model. After trehalose treatment, aggregate formation, soluble ataxin-3 protein levels and cell viability were evaluated in HEK293T cells overexpressing ataxin-3-15Q or ataxin-3-77Q. We also explored the mechanism by which trehalose affects autophagy and stress pathways. A filter trap assay showed that trehalose decreased the number of aggregates formed by mutant ataxin-3 containing an expanded polyQ tract. Western blot and Cell Counting Kit-8 (CCK-8) results demonstrated that trehalose also reduced the ataxin-3 protein levels and was safe for ataxin-3-expressing cells, respectively. Western blot and total antioxidant capacity assays suggested that trehalose had great therapeutic potential for treating SCA3, likely through its antioxidant activity. Our data indicate that trehalose plays a neuroprotective role in SCA3 by inhibiting the aggregation and reducing the protein level of ataxin-3, which is also known to protect against oxidative stress. These findings provide a new insight into the possibility of treating SCA3 with trehalose and highlight the importance of inducing autophagy in SCA3., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Acute gouty arthritis (AGA) is classified as 'arthritis' in traditional Chinese medicine (TCM) theory. Shirebi granules (SGs), derived from the classic prescription SiMiaoWan, exerts satisfying therapeutic efficacy in ameliorating AGA clinically. However, the underlying mechanisms of SGs against AGA remain unclarified., Methods: AGA-related biological processes, signal pathways and biomarker genes were mined from the GEO database through bioinformatics. SGs components were systematically recognized using the UPLC-Q-TOF-MS/MS. A correlation network was established based on the biomarker genes and the chemical components, from which the signal pathway used for further study was selected. Finally, we established an AGA model using SD rats injected with monosodium urate (MSU) in the ankle joint for experimental validation. A combination of behavioral tests, H&E, safranin O- fast green, western blotting, and immunofluorescence were employed to reveal the mechanism of action of SGs on AGA., Results: The deterioration of AGA was significantly related to the imbalance between immunity and inflammation, neutrophil chemotaxis and inflammatory factor activation. HDAC5, PRKCB, NFκB1, MPO, PRKCA, PIK3CA were identified to be the candidate targets of SGs against AGA, associated with neutrophil extracellular traps (NETs) signal pathway. Animal experiments demonstrated that SGs effectively repaired cartilage damage, blocked TLR4 activation, and inhibited the expression of NETs indicators and inflammatory factors. In addition, SGs prominently alleviated joint redness and swelling, improved joint dysfunction, inhibited inflammatory infiltration of AGA rats., Conclusion: Our data reveal that SGs may effectively alleviate the disease severity of AGA by suppressing NETs-promoted imbalance between immunity and inflammation., (© 2024. The Author(s).)

Background: Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks., Methods: We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs., Results: Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks., Conclusions: For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks., (© 2024. The Author(s).)

Epigenetic clocks based on DNA methylation have been known as biomarkers of aging, including principal component (PC) clocks representing the degree of aging and DunedinPACE representing the pace of aging. Prior studies have shown the associations between epigenetic aging and T2DM, but the results vary by epigenetic age metrics and people. This study explored the associations between epigenetic age metrics and T2DM or glycemic traits, based on 1070 twins (535 twin pairs) from the Chinese National Twin Registry. It also explored the temporal relationships of epigenetic age metrics and glycemic traits in 314 twins (157 twin pairs) who participated in baseline and follow-up visits after a mean of 4.6 years. DNA methylation data were used to calculate epigenetic age metrics, including PCGrimAge acceleration (PCGrimAA), PCPhenoAge acceleration (PCPhenoAA), DunedinPACE, and the longitudinal change rate of PCGrimAge/PCPhenoAge. Mixed-effects and cross-lagged modelling assessed the cross-sectional and temporal relationships between epigenetic age metrics and T2DM or glycemic traits, respectively. In the cross-sectional analysis, positive associations were identified between DunedinPACE and glycemic traits, as well as between PCPhenoAA and fasting plasma glucose, which may be not confounded by shared genetic factors. Cross-lagged models revealed that glycemic traits (fasting plasma glucose, HbA1c, and TyG index) preceded DunedinPACE increases, and TyG index preceded PCGrimAA increases. Glycemic traits are positively associated with epigenetic age metrics, especially DunedinPACE. Glycemic traits preceded the increases in DunedinPACE and PCGrimAA. Lowering the levels of glycemic traits may reduce DunedinPACE and PCGrimAA, thereby mitigating age-related comorbidities., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Our previous study showed that elevated preoperative thyroglobulin (pre-Tg) level predicted the risk of developing radioiodine refractory in PTC patients. In the present study, we aimed to evaluate the prognostic value of pre-Tg in papillary thyroid microcarcinoma (PTMC). After a specific inclusion and exclusion criteria were applied, a total of 788 PTMCs were enrolled from Jiangyuan Hospital affiliated to Jiangsu Institute of Nuclear Medicine between Jan 2015 and Dec 2019. Among them, 107 PTMCs were treated with radioiodine therapy (RAIT) and the response to therapy was grouped as excellent response (ER), and non-excellent response (NER: indeterminate response, IDR and biochemical incomplete response, BIR). Multivariable logistic regression was used to identify predictors for the response of RAIT in PTMCs. Higher pre-Tg levels were detected in PTMCs with RAIT as compared with PTMCs without RAIT (p=0.0018). Higher levels of pre-Tg were also found in patients with repeated RAIT as compared with patients with single RAIT (p<0.0001). Furthermore, pre-Tg level was higher in PTMC with IDR (n=16) and much higher in BIR (n=9) as compared with patients with ER (n=82, p=0.0003) after RAIT. Multivariate analysis showed that pre-Tg level over 16.79 ng/ml [OR: 6.55 (2.10-20.39), p=0.001] was the only independent predictor for NER in PTMC with RAIT. We found that high level of pre-Tg predicted a poor RAIT outcome in PTMC. Our finding explores a prospective way in identifying high-risk PTMCs with poor response to RAIT., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: Assessment of plaque stenosis severity allows better management of carotid source of stroke. Our objective is to create a deep learning (DL) model to segment carotid intima-media thickness and plaque and further automatically calculate plaque stenosis severity on common carotid artery (CCA) transverse section ultrasound images., Methods: Three hundred and ninety images from 376 individuals were used to train (235/390, 60%), validate (39/390, 10%), and test (116/390, 30%) on a newly proposed CANet model. We also evaluated the model on an external test set of 115 individuals with 122 images acquired from another hospital. Comparative studies were conducted between our CANet model with four state-of-the-art DL models and two experienced sonographers to re-evaluate the present model's performance., Results: On the internal test set, our CANet model outperformed the four comparative models with Dice values of 95.22% versus 90.15%, 87.48%, 90.22%, and 91.56% on lumen-intima (LI) borders and 96.27% versus 91.40%, 88.94%, 91.19%, and 92.88% on media-adventitia (MA) borders. On the external test set, our model still produced excellent results with a Dice value of 92.41%. Good consistency of stenosis severity calculation was observed between CANet model and experienced sonographers, with Intraclass Correlation Coefficient (ICC) of 0.927 and 0.702, Pearson's Correlation Coefficient of 0.928 and 0.704 on internal and external test set, respectively., Conclusions: Our CANet model achieved excellent performance in the segmentation of carotid IMT and plaques as well as automated calculation of stenosis severity., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The emerging high-frame-rate vector flow imaging provides a new way of hemodynamic evaluation for complex blood flow. This study was aimed at exploring quantitatively the characteristics of complex flow with turbulence (Tur) index and analyzing flow patterns in atherosclerotic internal carotid artery stenosis (ICAS) using high-frame-rate vector flow imaging., Methods: This study prospectively included 60 patients with ICAS. Tur values in different segments of stenosis and cardiac phases were compared. Spearman correlation analysis was performed between clinical plaque characteristics with turbulence grading by ln(Tur). Three complex flow patterns were qualitatively drawn on vector flow mode, and the rates of detection of flow patterns in different stenosis groups and ulceration groups were compared., Results: Highly disordered blood flow was observed in the stenotic (Tur [M, QR] = 12.5%, 21.5%) and distal segment (15.4%, 27.2%), particularly during systole (21.0%, 30.7%, 33.3%, 38.7%, p < 0.05). Spearman correlation analysis revealed that stenosis rate was correlated with turbulence grading in the stenotic (ρ = 0.65, p < 0.05) and distal segment (ρ = 0.79, p < 0.05), and ulcer formation was correlated with turbulence grading in the stenotic segment (ρ = 0.58, p < 0.05). The overall rate of detection of three flow patterns was higher in the severe stenosis group (22/22) versus the mild to moderate stenosis group (21/38) (p < 0.001) and in the ulcer group (21/23) versus the non-ulcer group (23/37) (p < 0.001)., Conclusion: High-frame-rate vector flow imaging was helpful in assessing the severity and characteristics of flow turbulence. Lumen geometric factors could affect flow turbulence and blood flow patterns around the plaque. This would provide important hemodynamic information for the detection of high-risk plaque., Competing Interests: Conflict of interest Y.D. is employed by Mindray. The other authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

This paper takes ethnic minority villages in Yunnan province of China, which have significant characteristics of multi-ethnic integration, as the research object. Through various spatial statistical analysis methods, we analyzed the overall distribution characteristics of ethnic villages in Yunnan, the distribution difference among various ethnic groups, and the influencing factors of the distribution pattern. It was found that: (1) The ethnic minority villages in Yunnan generally exhibit a kernel density characteristic of "three concentrated areas and multiple scattered points" and distribution characteristic of "hot spots in the west and cold spots in the east". Each ethnic group has a relatively concentrated region, presenting significant ethnic autocorrelation. (2) The differences in the relationship between villages and landscape among various ethnic groups have given rise to a unique three-dimensional distribution pattern, which is relate to ethnic origin and livelihood culture. Meanwhile, Han traditional villages tend to occupy areas with relatively better geographical conditions. (3) Natural factors, such as topographic relief, the distance between ethnic villages and rivers, and elevation, have a significant impact on the distribution of ethnic villages in Yunnan. Meanwhile, test results of social and human factors, including the distance from central cities, per capita GDP, and the gross annual output values of primary industry, indicate that the development of social economy and the promotion of urbanization pose challenges to the preservation of ethnic villages., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Xiao Dawei reports financial support was provided by 10.13039/501100001809National Natural Science Foundation of China (51778232). Zhuo Xiaolan reports financial support was provided by Guangdong Basic and Applied Basic Research Foundation (2023A1515011702). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Accurate and efficient bacterial typing methods are crucial to microbiology. Fourier transform infrared (FT-IR) spectroscopy enables highly distinguishable fingerprint identification of closely related bacterial strains by producing highly specific fingerprints of bacteria, which is increasingly being considered as an alternative to genotypic methods, such as pulsed field gel electrophoresis (PFGE) and whole genome sequencing (WGS), for bacterial typing. Compared with genotypic methods, FT-IR has significant advantages of convenient operation, fast speed, and low cost. Fundamental research into the detection limit based on optimized analytical conditions for FT-IR bacterial typing, which can avoid excessive bacterial culture time or sampling volume, is particularly important, especially in clinical practice. However, the corresponding parameters have not been fully investigated. In this study, we developed a simplified and reliable procedure for sample preparation, optimized the data analysis procedure, and evaluated the FT-IR detection limit based on the above conditions. In particular, we combined the film mold and calcium fluoride plate for sample preparation. We evaluated the detection limit (about 10 8 CFU/mL) after parameter optimization using hierarchical cluster analysis (HCA) and artificial neural network (ANN). The optimization and evaluation of these key fundamentals will better promote future application of FT-IR-based bacterial typing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hemicellulose is a highly abundant, ubiquitous, and renewable natural polysaccharide, widely present in agricultural and forestry residues. The enzymatic hydrolysis of hemicellulose has generally been accomplished using β-xylosidases, but concomitantly increasing the stability and activity of these enzymes remains challenging. Here, we rationally engineered a β-xylosidase from Bacillus clausii to enhance its stability by computation-aided design combining ancestral sequence reconstruction and structural analysis. The resulting combinatorial mutant rXYLO M25I/S51L/S79E exhibited highly improved robustness, with a 6.9-fold increase of the half-life at 60 °C, while also exhibiting improved pH stability, catalytic efficiency, and hydrolytic activity. Structural analysis demonstrated that additional interactions among the propeller blades in the catalytic module resulted in a much more compact protein structure and induced the rearrangement of the opposing catalytic pocket to mediate the observed improvement of activity. Our work provides a robust biocatalyst for the hydrolysis of agricultural waste to produce various high-value-added chemicals and biofuels.

Background and Objective: The incidence of stroke is rising, and it is the second major cause of mortality and the third leading cause of disability around the globe. The goal of this study was to rapidly and accurately identify carotid plaques and automatically quantify plaque burden using our automated tracking and segmentation US-video system., Methods: We collected 88 common carotid artery transection videos (11048 frames) with a history of atherosclerosis or risk factors for atherosclerosis, which were randomly divided into training, test, and validation sets using a 6:3:1 ratio. We first trained different segmentation models to segment the carotid intima and adventitia, and calculate the maximum plaque burden automatically. Finally, we statistically analyzed the plaque burden calculated automatically by the best model and the results of manual labeling by senior sonographers., Results: Of the three Artificial Intelligence (AI) models, the Robust Video Matting (RVM) segmentation model's carotid intima and adventitia Dice Coefficients (DC) were the highest, reaching 0.93 and 0.95, respectively. Moreover, the RVM model has shown the strongest correlation coefficient (0.61±0.28) with senior sonographers, and the diagnostic effectiveness between the RVM model and experts was comparable with paired-t test and Bland-Altman analysis [P= 0.632 and ICC 0.01 (95% CI: -0.24~0.27), respectively]., Conclusion: Our findings have indicated that the RVM model can be used in ultrasound carotid video. The RVM model can automatically segment and quantify atherosclerotic plaque burden at the same diagnostic level as senior sonographers. The application of AI to carotid videos offers more precise and effective methods to evaluate carotid atherosclerosis in clinical practice.

Introduction: At present, early detection of the potential risk of atherosclerosis and prevention is of great significance to reduce the occurrence of stroke., Aim: This study aims to explore the value of combining the wall shear stress measured by ultrasound vector flow imaging technique and sound touch elastography of common carotid artery in normal adults using the Mindray Resona 7 ultrasound system., Methods: Forty volunteers (mean age 39.5 y, 23 females, 17 males) were divided into four groups according to their age. All volunteers underwent ultrasound carotid artery examination, and the values of wall shear stress and elasticity on the posterior wall of the common carotid artery were measured using advanced imaging functions, vector flow imaging technique, and sound touch elastography., Results: Different cut-off values of wall shear stress were used to investigate the significance between two groups with corresponding sound touch elastography values. It can be seen that the statistical difference could be found when the mean wall shear stress was larger than 1.5 Pa approximately (statistical significance was defined when P < 0.05), and the sound touch elastography value was positively correlated with the wall shear stress value., Conclusion: This study reveals that the combination of wall shear stress and sound touch elastography is an effective and feasible method for assessing carotid artery health. When the mean wall shear stress value is over 1.5 Pa, the corresponding sound touch elastography value increases significantly. The risk of atherosclerosis increases with the stiffness of blood vessel walls.

Introduction: The aim of the study was to evaluate characteristics and provide the normal values of wall shear stress (WSS) and flow turbulence (Tur), and the relationship between them in the carotid bifurcation based on an ultrasound vector flow imaging (V Flow) in healthy adults., Methods: Max and mean WSS and Tur values at three segments (initial segments of internal and external carotid arteries [IICA and IECA]; distal segment of common carotid artery [DCCA]), both in anterior and posterior walls, were successfully obtained in 56 healthy adults, using ultrasound V Flow function. Relationship between mean WSS and Tur was further explored., Results: The mean WSS value was 0.71 Pa, 0.86 Pa, and 0.96 Pa at IICA, IECA, and DCCA, respectively (IICA &lt; IECA &lt; DCCA, p &lt; 0.05). The mean Tur value was 13.85%, 5.46%, and 4.17% at IICA, IECA, and DCCA, respectively (IICA &gt; IECA &gt; DCCA, p &lt; 0.05). A cutoff value (WSS = 0.4 Pa) was selected and Tur values were significantly higher in group with WSS cutoff value &lt;0.4 Pa than group with WSS cutoff value ≥0.4 Pa (p &lt; 0.01)., Conclusion: WSS and Tur are moderately negatively correlated, which can be used in the quantitative evaluation of carotid bifurcation and could be a potential dual-parameter tool in the clinical research for early detection of carotid atherosclerosis., (© 2023 S. Karger AG, Basel.)

Aim: To identify the psychological distress (PD)-associated 5'-cytosine-phosphate-guanine-3' sites (CpGs), and investigate the temporal relationship between dynamic changes in DNA methylation (DNAm) and PD., Methods: This study included 1084 twins from the Chinese National Twin Register (CNTR). The CNTR conducted epidemiological investigations and blood withdrawal twice in 2013 and 2018. These included twins were used to perform epigenome-wide association studies (EWASs) and to validate the previously reported PD-associated CpGs selected from previous EWASs in PubMed, Embase, and the EWAS catalog. Next, a cross-lagged study was performed to examine the temporality between changes in DNAm and PD in 308 twins who completed both 2013 and 2018 surveys., Results: The EWAS analysis of our study identified 25 CpGs. In the validation analysis, 741 CpGs from 29 previous EWASs on PD were selected for validation, and 101 CpGs were validated to be significant at a false discovery rate <0.05. The cross-lagged analysis found a unidirectional path from PD to DNAm at 14 CpGs, while no sites showed significance from DNAm to PD., Conclusions: This study identified and validated PD-related CpGs in a Chinese twin population, and suggested that PD may be the cause of changes in DNAm over time. The findings provide new insights into the molecular mechanisms underlying PD pathophysiology., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Circulating tumor cells (CTCs) are tumor cells that spontaneously detach from the primary focus, and early detection and characterization of CTCs is vital for cancer diagnosis and appropriate treatment. Current methods commonly use EpCAM to capture CTCs, but this results in a loss of information on other CTC subsets (EpCAM-negative cells) due to the heterogeneity of CTCs. Here, we report a novel microfluidic device that integrates the capture and release of heterogeneous CTCs directly from whole blood. A spiral chip was designed for the separation of differently sized cells, and larger CTCs were effectively separated from smaller blood cells with a 98% recovery rate. CD146-containing magnetic beads were used to complement the EpCAM-based CTC capture methods, and the capture efficiency of Fe 3 O 4 @Gelatin@CD146/EpCAM increased by 20% over Fe 3 O 4 @Gelatin@EpCAM. Finally, MMP-9 was employed to release CTCs with high efficiency and less damage by degrading gelatins on the surface of Fe 3 O 4 . The established method was successfully applied to CTC capture and release in a simulated patient's whole blood. The developed method achieved enhanced capture and high activity release of heterogeneous CTCs with less interference by blood cells, which contributes to the early detection and clinical downstream analysis of CTCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Thyroid cancer is one of the most common endocrine malignancies. Differentiated thyroid cancer (DTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). DTC generally has a good prognosis. However, tumor dedifferentiation or defect in certain cell death mechanism occurs in a subset of DTC patients, leading to RAI resistance. Therefore, developing novel therapeutic approaches that enhance RAI sensitivity are still warranted. We found that curcumin, an active ingredient in turmeric with anti-cancer properties, rapidly accumulated in the mitochondria of thyroid cancer cells but not normal epithelial cells. Curcumin treatment triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a robust decrease in mitochondrial mass and proteins, indicating that curcumin selectively induced mitophagy in thyroid cancer cells. In addition, curcumin-induced mitophagic cell death and its synergistic cytotoxic effect with radioiodine could be attenuated by autophagy inhibitor, 3-methyladenine (3-MA). Interestingly, the mechanism of mitophagy-inducing potential of curcumin was its unique mitochondria-targeting property, which induced a burst of SDH activity and excessive ROS production. Our data suggest that curcumin induces mitochondrial dysfunction and triggers lethal mitophagy, which synergizes with radioiodine to kill thyroid cancer cells., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled “Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment”. No conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright © 2023. Published by Elsevier Ltd.)

Microbes are usually present as a specific microbiota, and their classification remains a challenge. MALDI-TOF MS is particularly successful in library-based microbial identification at the species level as it analyzes the molecular weight of peptides and ribosomal proteins. FT-IR allows more accurate classification of bacteria at the subspecies level due to the high sensitivity, specificity and repeatability of FT-IR signals from bacteria, which is not achievable with MALDI-TOF MS. Previous studies have shown that more accurate identification results can be obtained by the fusion of FT-IR and MALDI-TOF MS spectral data. Here, we constructed 20 groups of model microbiota samples and used FT-IR, MALDI-TOF MS, and their fusion data to classify them. Hierarchical clustering analysis (HCA) showed that the classification accuracy of FT-IR, MALDI-TOF MS, and the fusion data was 85%, 90%, and 100%, respectively. These results indicate that both FT-IR and MALDI-TOF MS can effectively classify specific microbiota, and the fusion of their spectral data could improve the classification accuracy. The FT-IR and MALDI-TOF MS data fusion strategy may be a promising technology for specific microbiota classification.

Breast cancer (BC) is a complex disease with high variability and no specific tumor markers available for diagnosis. Exosomes contain rich maternal tumor information and are a novel non-invasive biomarker with the potential for cancer diagnosis and prognosis. However, analysis of exosomal protein markers in blood samples is challenging due to lengthy sample workups and insufficient sensitivity. To address this difficulty, we developed a novel filter-electrochemical microfluidic chip (FEMC) to detect and classify BC directly in whole blood without requiring heavy purification methods. In our system, exosome enrichment was performed using a dual filtration system. The target was directed through a curved channel onto four screen-printed electrodes (SPEs), where it was captured by the previously modified antibodies. Simultaneously, Zr-MOFs encapsulated with a large number of methylene blue molecules (MB@UiO-66) were absorbed on the surface of exosomes due to the high affinity for phosphate groups. This process leads to the amplification of electrical signals. The approach demonstrated that the utilization of BC exosome-associated tumor biomarkers (i.e., PMSA, EGFR, CD81, and CEA), enabled the classification of various BC mouse models samples and clinical BC samples. The entire FEMC assay was completed in 1 h with a limit of detection of 1 × 10 4 particles/mL. Thus, the FEMC assay can provide real-time detection information, allowing timely and better-informed opportunities for clinical BC diagnosis and typing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.NO., (Copyright © 2023. Published by Elsevier B.V.)

Low mass transfer efficiency and unavoidable matrix effects seriously limit the development of rapid and accurate determination of biosensing systems. Herein, we have successfully constructed an ultra-rapid nanoconfinement-enhanced fluorescence clinical detection platform based on machine learning (ML) and DNA xerogel "probe", which was performed by detecting neutrophil gelatinase-associated lipocalin (NGAL, protein biomarker of acute kidney injury). By regulating pore sizes of the xerogels, the transfer of NGAL in xerogels can approximate that in homogeneous solution. Due to electrostatic attraction of the pore entrances, NGAL rapidly enriches on the surface and inside the xerogels. The reaction rate of NGAL and aptamer cross-linked in xerogels is also accelerated because of the nanoconfinement effect-induced increasing reactant concentration and the enhanced affinity constant K D between reactants, which can be promoted by ∼667-fold than that in bulk solution, thus achieving ultra-rapid detection (ca. 5 min) of human urine. The platform could realize one-step detection without sample pretreatments due to the antiligand exchange effect on the surface of N-doped carbon quantum dots (N-CQDs) in xerogels, in which ligand exchange between -COOH and underlying interfering ions in urine will be inhibited due to higher adsorption energy of -COOH on the N-CQD surface relative to the interfering ions. Based on the ML-extended program, the real-time analysis of the urine fluorescence spectra can be completed within 2 s. Interestingly, by changing DNA, aptamer sequences, or xerogel fluorescence intensities, the detection platform can be customized for targeted diseases.

Purpose: To investigate the distribution of 50 layers of corneal densitometry and related factors., Methods: Clinical data, including age, sex, central corneal thickness, corneal keratometry, and diopters, were collected from 102 healthy participants (102 eyes) in this retrospective study. The cornea was divided into 50 layers, and densitometry of each layer at 19 points was measured by the Pentacam. The value versus the depth curve was plotted. Paired-sample t test and one-way analysis of variance were used to compare densitometry in different regions or depth. Statistical significance was defined as P < .05., Results: The densitometry values of the Bowman membrane (10-14% depth), anterior stroma (14-30% depth), epithelium (0-10% depth), and Descemet membrane (94-98% depth) decreased sequentially, and the densitometry values of the middle and posterior stroma (30-94% depth) and endothelium (98-100% depth) were the lowest. The higher the degree of astigmatism, the higher the second densitometry peak (R = 0.277, P < .001). The densitometry values of the vertex and superior parts of the cornea were higher than those in the periphery and inferior parts, respectively (all P < .001). In the Bowman membrane, the densitometry is lowest in the inferior nasal part, while in the Descemet membrane, it is lowest in the inferior temporal part., Conclusion: Two densitometry peaks appeared near the Bowman membrane and Descemet membrane. For different depths, the distribution of densitometry within a layer is different. We provide a methodological reference and data basis for corneal research based on local changes in densitometry, and help understand the details of corneal structure from an optical perspective through detailed layering and zoning analysis of densitometry., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

To systematically evaluate the clinical effect of wavefront-guided laser in situ keratomileusis (WFG-LASIK) and small incision lenticule extraction (SMILE) in terms of refractive errors and high-order aberrations. A systematic literature search of PubMed, EMBASE, the Cochrane Library, Web of Science and China National Knowledge Internet was performed to identify studies evaluating the clinical outcomes of SMILE and WFG-LASIK ended in May 2022. Meta-analyses were performed according to the PRISMA guidelines. The risk of bias of the RCTs was evaluated using the Cochrane Handbook criteria, and the quality of the non-randomised controlled studies was assessed using the Newcastle-Ottawa Scale. In total, 1385 eyes (SMILE group, 750 eyes; WFG-LASIK group, 635 eyes) from 12 studies were included. The meta-analysis demonstrated that spherical aberration was smaller in the SMILE group than in the WFG-LASIK group (standardised mean difference [SMD]: -0.34, 95% confidence interval [CI]: -0.47, -0.22; p < 0.00001), and that the postoperative values of vertical coma (SMD: 0.83; 95% CI: 0.63, 1.03; p < 0.00001) and trefoil (SMD: 0.37; 95% CI: 0.02, 0.72; p = 0.04) were higher in the SMILE group compared to the WFG LASIK group. There were no significant differences in the clinical outcomes and the values of induced total higher order aberrations between the WFG-LASIK and SMILE groups (SMD: 0.05; 95% CI: -0.09, 0.19; p = 0.47). Both SMILE and WFG-LASIK were found to be safe, effective, and predictable. SMILE may induce more vertical coma and trefoil, whereas WFG LASIK may induce more spherical aberrations, but no significant differences were found in the total higher order aberrations between SMILE and WFG-LASIK., (© 2023 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

A simple yet powerful approach to obtain structural color is the amorphous assembly of colloidal spheres, which is also referred to as the amorphous photonic structure or photonic glasses (PGs). Additionally, the functionalization of the colloidal spheres as building blocks can further endow the resulting PGs with multifunctions. Herein, we have developed a facile strategy to prepare SiO 2 colloidal spheres with concentrically embedded carbon dots (CDs). Notably, the CDs are prepared and silane-functionalized simultaneously, which enables the perfect incorporation of CDs into the Si-O network during the Stöber reaction and thus leads to the formation of a concentric SiO 2 /CD interlayer within the obtained SiO 2 spheres. Moreover, the obtained SiO 2 /CD spheres can be applied as photonic pigments by assembling them into PGs, which exhibit structural color under daylight and fluorescence under UV illumination. With incorporation of carbon black, the structural color saturation and fluorescence intensity can be further manipulated. Owing to the combination of structural colored PGs and fluorescent CDs, our study can offer inspiration for color- and fluorescence-related applications such as sensing, in vivo imaging, LEDs, and anticounterfeiting.

Background: We initiated the Fujian Tulou Pedigree-based Cohort (FTPC) as the integration of extended pedigrees and prospective cohort to clarify the genetic and environmental risk factors of cardiometabolic diseases., Methods: FTPC was carried out in Nanjing County, Fujian Province, China from August 2015 to December 2017 to recruit probands with the same surnames and then enroll their first-degree and more distant relatives. The participants were asked to complete questionnaire interview, physical examination, and blood collection. According to the local genealogical booklets and family registry, we reconstructed extended pedigrees to estimate the heritability of cardiometabolic traits. The follow-up of FTPC is scheduled every 5 years in the future., Results: The baseline survey interviewed 2,727 individuals in two clans. A total of 1,563 adult subjects who completed all baseline examinations were used to reconstruct pedigrees and 452 extended pedigrees were finally identified, including one seven-generation pedigree, two five-generation pedigrees, 23 four-generation pedigrees, 186 three-generation pedigrees, and 240 two-generation pedigrees. The average age of the participants was 57.4 years, with 43.6% being males. The prevalence of hypertension, diabetes and dyslipidemia in FTPC were 49.2, 10.0, and 45.2%, respectively. Based on the pedigree structure, the heritability of systolic blood pressure, diastolic blood pressure, fast blood glucose, total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein was estimated at 0.379, 0.306, 0.386, 0.452, 0.568, 0.852, and 0.387, respectively., Conclusion: As an extended pedigree cohort in China, FTPC will provide an important source to study both genetic and environmental risk factors prospectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Ye, Huang, Huang, Gao, Wang, Li, Zhou, Jiang, Wang, Yu, Lv, Wu, Huang, Cao, Yan, Zheng, Wu and Li.)

Purpose: To investigate the feasibility of high-frame-rate vector flow imaging (HiFR-VFI) compared to ultrasound color Doppler flow imaging (CDFI) for precisely evaluating flow characteristics in the carotid bifurcation (CB) of presumed healthy adults., Methods: Forty-three volunteers were assessed for flow characteristics and their extensions using HiFR-VFI and CDFI in CBs. The flow patterns were classified according to the streamlines in HiFR-VFI and quantitatively measured using an innovative turbulence index (Tur-value). Interobserver agreement was also assessed., Results: HiFR-VFI was consistent with CDFI in detecting laminar and nonlaminar flow in 81.4% of the cases; however, in 18.6% of the cases, only HiFR-VFI identified the nonlaminar flow. HiFR-VFI showed a larger extension of complex flow (0.37 ± 0.26 cm 2 ) compared to CDFI (0.22 ± 0.21 cm 2 ; p < 0.05). The flow patterns were classified into four types: 3 type-I (laminar flow), 35 type-II (rotational flow), 27 type-III (reversed flow), and 5 type-IV (complex flow). The Tur-value of type-IV (50.03 ± 14.97)% is larger than type-III (44.57 ± 8.89)%, type-II (16.30 ± 8.16)%, and type-I (1.48 ± 1.43)% (p < 0.05). Two radiologists demonstrated almost perfect interobserver agreement on recognizing the change of streamlines (κ = 0.81, p < 0.001). The intraclass correlation coefficient of the Tur-value was 0.98., Conclusion: HiFR-VFI can reliably characterize complex hemodynamics with quantitative turbulence measurement and may be an auxiliary diagnostic tool for assessing atherosclerotic arterial disease., (© 2023 Wiley Periodicals LLC.)

The behavior of heavy metals in contaminated sediment is of ecological significance considering the change of pH caused by ocean acidification. This study investigated the mobility of Cd, Cu, Ni, Pb, Fe, and Mn under experimental conditions for seawater acidification via enrichment of CO 2 gas at different reaction set-ups. The results indicated that the concerned metals behaved differently in the water compared to the sediment. The heavy metals were considerably transferred from sediment to seawater, and the resultant intensity was controlled by the degree of acidification and the chemical state of specific metals. Moreover, labile fractions of heavy metals in sediments were more susceptible to acidification than other fractions. These findings were observed and confirmed using real-time monitoring conducted via the diffusion gradient technique (DGT). Overall, the results of this study provided new insights into exploring the coupling risk of heavy metals with ocean acidification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

MALDI-TOF MS is well-recognized for single microbial identification and widely used in research and clinical fields due to its specificity, speed of analysis, and low cost of consumables. Multiple commercial platforms have been developed and approved by the U.S. Food and Drug Administration. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has been used for microbial identification. However, microbes can present as a specific microbiota, and detection and classification remain a challenge. Here, we constructed several specific microbiotas and tried to classify them using MALDI-TOF MS. Different concentrations of nine bacterial strains (belonging to eight genera) constituted 20 specific microbiotas. Using MALDI-TOF MS, the overlap spectrum of each microbiota (MS spectra of nine bacterial strains with component percentages) could be classified by hierarchical clustering analysis (HCA). However, the real MS spectrum of a specific microbiota was different than that of the overlap spectrum of component bacteria. The MS spectra of specific microbiota showed excellent repeatability and were easier to classify by HCA, with an accuracy close to 90%. These results indicate that the widely used MALDI-TOF MS identification method for individual bacteria can be expanded to classification of microbiota. IMPORTANCE MALDI-TOF MS can be used to classify specific model microbiota. The actual MS spectrum of the model microbiota was not a simple superposition of every single bacterium in a certain proportion but had a specific spectral fingerprint. The specificity of this fingerprint can enhance the accuracy of microbiota classification., Competing Interests: The authors declare no conflict of interest.

Introduction: A growing body of evidence suggests that parental substance abuse, even prior to conception, may induce phenotypic changes in offspring. Parental opioid exposure has been shown to affect developmental processes, induce memory deficits, and lead to psycho-emotional disorders in offspring. However, how parental, especially paternal, chronic drug exposure affects offspring remains unexplored. Methods: Adult male rats were subjected to 31 days of heroin self-administration followed by mating with naïve females. Litter size and body weight of F1 offspring were recorded. Object-based attention tests, cocaine self-administration tests, and hot plate tests were used to test for potential effects of chronic paternal heroin seeking on cognition, reward, or analgesic sensitivity in the offspring. Results: Body weight and litter size of the heroin F1 generation were not altered compared to the saline F1 generation. Furthermore, paternal chronic heroin self-administration experience had no significant effect on object-based attention tests or cocaine self-administration behavior in either sex. However, in the hot plate test, although no difference in basal latency was found between the two groups in either sex, a significant increase in the analgesic effect of heroin was observed in the male heroin F1 generation. Conclusions: Taken together, these data provide evidence that paternal chronic heroin self-administration experience could sex-dimorphically increase the analgesic effect of heroin in male offspring, but had no significant effect on response to cocaine reinforcement or attentional behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Pan, Fan, Cui, Wang, Huang, Jiang, Ma, Wang, Liu and Le.)

Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Due to dedifferentiation of tumor cells, manifested by a decreased expression of iodide-handling genes in thyrocytes, some thyroid carcinomas lose their capability for radioiodine concentration and gradually develop radioactive iodine (RAI) resistance. This work aimed to investigate the role of tumor microenvironment (TME) in the process of tumor cell dedifferentiation., Materials and Methods: Bioinformatic analyses and subsequent immunohistochemistry (IHC) and western blot assays were performed in papillary thyroid carcinoma (PTC) and matched normal tissue. ELISA was used to assess the secretion of cytokines under the stimulation of pharmacological endoplasmic reticulum (ER) stress inducer., Results: Higher levels of pro-inflammatory cytokines, interleukin 6 (IL-6) and (C-X-C motif chemokine ligand 8 (CXCL8), were found in thyroid cancer tissues compared with matched normal tissues. ER stress, induced by stressful environmental stimuli, such as nutrient deprivation and hypoxia, occurred in thyroid tumors. Classic ER stress inducers, thapsigargin (Tg) and tunicamycin (Tm), promoted the expression of IL6 and CXCL8 in thyroid cancer cells at mRNA and protein levels. Of note, rIL-6 and rCXCL8 promoted the dedifferentiation of thyroid cancer cells or even non-transformed cells in an autocrine/paracrine manner, weakening radioiodine uptake ability of thyroid cancer cells. Intriguingly, sorafenib, a multiple kinase inhibitor (MKI), could potently suppress not only ER stress-induced but also basal expressions of IL-6 and CXCL8 in thyroid cancer cells., Conclusions: The inflammatory TME could regulate cell dedifferentiation, leading to loss of thyroid-specific gene expressions, through reciprocal interaction between thyroid tumor cells and follicular cells. Our study provides a new perspective on the mechanisms of how inflammatory TME affects DTC dedifferentiation., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled “Inflammatory tumor microenvironment of thyroid cancer promotes cellular dedifferentiation and silencing of iodide-handling genes expression”. No conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Aging plays a crucial role in the mechanisms of the impacts of genetic and environmental factors on blood pressure and serum lipids. However, to our knowledge, how the influence of genetic and environmental factors on the correlation between blood pressure and serum lipids changes with age remains to be determined. In this study, data from the Chinese National Twin Registry (CNTR) were used. Resting blood pressure, including systolic and diastolic blood pressure (SBP and DBP), and fasting serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) were measured in 2378 participants (1189 twin pairs). Univariate and bivariate structural equation models examined the genetic and environmental influences on blood pressure and serum lipids among three age groups. All phenotypes showed moderate to high heritability (0.37-0.59) and moderate unique environmental variance (0.30-0.44). The heritability of all phenotypes showed a decreasing trend with age. Among all phenotypes, SBP and DBP showed a significant monotonic decreasing trend. For phenotype-phenotype pairs, the phenotypic correlation (Rph) of each pair ranged from -0.04 to 0.23, and the additive genetic correlation (Ra) ranged from 0.00 to 0.36. For TC&SBP, TC&DBP, TG&SBP and TGs&DBP, both the Rph and Ra declined with age, and the Ra difference between the young group and the older adult group is statistically significant ( p < .05). The unique environmental correlation (Re) of each pair did not follow any pattern with age and remained relatively stable with age. In summary, we observed that the heritability of blood pressure was affected by age. Moreover, blood pressure and serum lipids shared common genetic backgrounds, and age had an impact on the phenotypic correlation and genetic correlations.

Accurate identification of intussusception in children is critical for timely non-surgical management. We propose an end-to-end artificial intelligence algorithm, the Children Intussusception Diagnosis Network (CIDNet) system, that utilizes ultrasound images to rapidly diagnose intussusception. 9999 ultrasound images of 4154 pediatric patients were divided into training, validation, test, and independent reader study datasets. The independent reader study cohort was used to compare the diagnostic performance of the CIDNet system to six radiologists. Performance was evaluated using, among others, balance accuracy (BACC) and area under the receiver operating characteristic curve (AUC). The CIDNet system performed the best in diagnosing intussusception with a BACC of 0.8464 and AUC of 0.9716 in the test dataset compared to other deep learning algorithms. The CIDNet system compared favorably with expert radiologists by outstanding identification performance and robustness (BACC:0.9297; AUC:0.9769). CIDNet is a stable and precise technological tool for identifying intussusception in ultrasound scans of children., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Purpose: To assess the distribution characteristics and related factors of stress-strain index (SSI) values and discuss changes in biomechanical parameters, including SSI, after small incision lenticule extraction (SMILE) surgery. Methods: This study included 253 patients who underwent SMILE (253 eyes). SSI and other biomechanical parameters were measured using corneal visualization Scheimpflug technology before and 3 months after surgery. The data collected included SSI, central corneal thickness (CCT), and eight other dynamic corneal response parameters. The Kolmogorov-Smirnov test, Pearson and partial correlation analyses, and paired-sample t -tests were used for statistical analyses. Results: Both pre-op SSI and ΔSSI follow a normal distribution, while post-op SSI does not follow a normal distribution. The decline in SSI after SMILE surgery was not statistically significant, and the data dispersion of SSI after SMILE surgery was close to that before surgery ( p > 0.05). No statistical correlation was noted between SSI values and age and pre-op CCT (all p > 0.05). However, both pre- and post-op SSI values decreased with increasing degree of myopia (all p < 0.05), and weakly correlated with preoperative intraocular pressure and biomechanically corrected intraocular pressure (all p < 0.05). Other biomechanical parameters changed significantly after surgery (all p < 0.001). After SMILE, the magnitude of the deformation at the highest concave, deformation ratio, and integral radius increased significantly (all p < 0.001), while the Ambrosio relational thickness horizontal, stiffness parameter A1, and Corvis biomechanical index decreased significantly ( p < 0.001). Conclusion: SSI, which reflects essential corneal material attributes, differs from other corneal biomechanical parameters and remains stable before and after SMILE surgery, and can be used as an indicator to evaluate changes in corneal material properties after SMILE surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Zhao and Wang.)

Objectives: To assess the feasibility and performance of Turbulence (Tur) index as a quantitative tool for carotid artery flow turbulence; to detect and compare the blood flow patterns of common carotid artery (CCA) and carotid bulb (CB) at different ages and cardiac phases in healthy adults, and thus interpret the evolvement of etiology difference between CCA and CB., Methods: Carotid flow characteristics of 40 healthy volunteers were evaluated quantitatively by a high-frame rate vector flow imaging. Three types of flow patterns were defined depending on the distributive range of complex flow during systole in CB. Comparison of mean Tur value in CCA and CB at different age groups and cardiac phases was performed. And the correlation between Tur value and the diameter ratio of proximal internal carotid artery to common carotid artery (DRpro-ica/cca) was tested., Results: Mean Tur values in CB were remarkably higher than that in CCA, whether during systole or diastole (P < .001). Meanwhile Tur values in CB during systole were significantly higher than that during diastole (P < .001). Flow complexity of CB showed variations among 40 participants especially in systole, whereas the flow pattern of CCA was relatively consistent. Mean Tur values were positively correlated with DRpro-ica/cca in CB (ρ = 0.69, P < .05)., Conclusions: V Flow imaging provided a reliable method-Tur, for quantitative analysis of carotid blood flow. It had potential to be further applied in distinguishing complex hemodynamic characteristics in high-risk people of carotid diseases for the risk stratification of cardiovascular events., (© 2022 American Institute of Ultrasound in Medicine.)

Background: Previous EWASs (Epigenome-Wide Association Studies) have reported hundreds of blood pressure (BP) associated 5'-cytosine-phosphate-guanine-3' (CpG) sites. However, their results were inconsistent. Longitudinal observations on the temporal relationship between DNA methylation and BP are lacking., Methods: A candidate CpG site association study for BP was conducted on 1072 twins in the Chinese National Twin Registry. PubMed and EMBASE were searched for candidate CpG sites. Cross-lagged models were used to assess the temporal relationship between BP and DNA methylation in 308 twins who completed 2 surveys in 2013 and 2018. Then, the significant cross-lagged associations were validated by adopting the Inference About Causation From Examination of Familial Confounding approach. Finally, to evaluate the cumulative effects of DNA methylation on the progression of hypertension, we established methylation risk scores based on BP-associated CpG sites and performed Markov multistate models., Results: 16 and 20 CpG sites were validated to be associated with systolic BP and diastolic BP, respectively. In the cross-lagged analysis, we detected that methylation of 2 CpG sites could predict subsequent systolic BP, and systolic BP predicted methylation at another 3 CpG sites. For diastolic BP, methylation at 3 CpG sites had significant cross-lagged effects for predicting diastolic BP levels, while the prediction from the opposite direction was observed at one site. Among these, 3 associations were validated in the Inference About Causation From Examination of Familial Confounding analysis. Using the Markov multistate model, we observed that methylation risk scores were associated with the development of hypertension., Conclusions: Our findings suggest the significance of DNA methylation in the development of hypertension.

Background: The prevalence of obesity and cardiometabolic diseases continues to rise globally and obesity is a significant risk factor for cardiometabolic diseases. However, to our knowledge, evidence of the relative roles of genes and the environment underlying obesity and cardiometabolic disease traits and the correlations between them are still lacking, as is how they change with age. Method: Data were obtained from the Chinese National Twin Registry (CNTR). A total of 1421 twin pairs were included. Univariate structural equation models (SEMs) were performed to evaluate the heritability of BMI and cardiometabolic traits, which included blood hemoglobin A1c (HbA1c), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Bivariate SEMs were used to assess the genetic/environmental correlations between them. The study population was divided into three groups for analysis: ≤50, 51−60, and >60 years old to assess the changes in heritability and genetic/environmental correlations with ageing. Results: Univariate SEMs showed a high heritability of BMI (72%) and cardiometabolic traits, which ranged from 30% (HbA1c) to 69% (HDL-C). With age increasing, the heritability of all phenotypes has different degrees of declining trends. Among these, BMI, SBP, and DBP presented significant monotonous declining trends. The bivariate SEMs indicated that BMI correlated with all cardiometabolic traits. The genetic correlations were estimated to range from 0.14 (BMI and LDL-C) to 0.39 (BMI and DBP), while the environmental correlations ranged from 0.13 (BMI and TC/LDL-C) to 0.31 (BMI and TG). The genetic contributions underlying the correlations between BMI and SBP and DBP, TC, TG, and HDL-C showed a progressive decrease as age groups increased. In contrast, environmental correlations displayed a significant increasing trend for HbA1c, SBP, and DBP. Conclusions: The findings suggest that genetic and environmental factors have essential effects on BMI and all cardiometabolic traits. However, as age groups increased, genetic influences presented varying degrees of decrement for BMI and most cardiometabolic traits, suggesting the increasing importance of environments. Genetic factors played a consistently larger role than environmental factors in the phenotypic correlations between BMI and cardiometabolic traits. Nevertheless, the relative magnitudes of genetic and environmental factors may change over time.

Investigators of previous cross-sectional epigenome-wide association studies (EWAS) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWAS have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNA methylation (DNAm) could be modified by smoking, drinking, and glycemic traits, which have broad impacts on genome-wide DNAm and result in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as twins are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and Embase for EWAS, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c, and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17, and 16 CpG sites from previous studies were validated for T2DM, HbA1c, and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 for 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. A total of 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none were from the other cross-lagged direction, indicating that CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed to explore the mediation effects of DNAm on the associations of smoking, drinking, and glycemic traits with T2DM. No significant mediations of DNAm in the associations linking smoking and drinking with T2DM were found. In contrast, our study suggested a potential role of DNAm of cg19693031, cg00574958, and cg04816311 in mediating the effect of altered glycemic traits on T2DM., (© 2022 by the American Diabetes Association.)

It is crucial to understand the genetic mechanisms and biological pathways underlying the relationship between obesity and serum lipid levels. Structural equation models (SEMs) were constructed to calculate heritability for body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and the genetic connections between BMI and the four classes of lipids using 1197 pairs of twins from the Chinese National Twin Registry (CNTR). Bivariate genomewide association studies (GWAS) were performed to identify genetic variants associated with BMI and lipids using the records of 457 individuals, and the results were further validated in 289 individuals. The genetic background affecting BMI may differ by gender, and the heritability of males and females was 71% (95% CI [.66, .75]) and 39% (95% CI [.15, .71]) respectively. BMI was positively correlated with TC, TG and LDL-C in phenotypic and genetic correlation, while negatively correlated with HDL-C. There were gender differences in the correlation between BMI and lipids. Bivariate GWAS analysis and validation stage found 7 genes ( LOC105378740 , LINC02506 , CSMD1 , MELK , FAM81A , ERAL1 and MIR144 ) that were possibly related to BMI and lipid levels. The significant biological pathways were the regulation of cholesterol reverse transport and the regulation of high-density lipoprotein particle clearance ( p < .001). BMI and blood lipid levels were affected by genetic factors, and they were genetically correlated. There might be gender differences in their genetic correlation. Bivariate GWAS analysis found MIR144 gene and its related biological pathways may influence obesity and lipid levels.

Objectives: To investigate the feasibility of the vector flow imaging (V Flow) technique to measure peripheral arterial hemodynamic parameters, including wall shear stress (WSS) and turbulence index (Tur) in healthy adults, and compare the results in different arteries., Materials and Methods: Fifty-two healthy adult volunteers were recruited in this study. The maximum and mean values of WSS, and the Tur values at early-systole, mid-systole, late-systole, and early diastole for total 156 normal peripheral arteries [common carotid arteries (CCA), subclavian arteries (SCA), and common femoral arteries (CFA)] were assessed using the V Flow technique., Results: The mean WSS values for CCA, SCA, and CFA were (1.66 ± 0.68) Pa, (0.62 ± 0.30) Pa, and (0.56 ± 0.27) Pa, respectively. The mean Tur values for CCA, SCA, and CFA were (0.46 ± 1.09%), (20.7 ± 9.06%), and (24.63 ± 17.66%), respectively. The CCA and SCA, as well as the CCA and CFA, showed statistically significant differences in the mean WSS and the mean Tur ( P < 0.01). The mean Tur values had a negative correlation with the mean WSS; the correlation coefficient between log(Tur) and WSS is -0.69 ( P < 0.05)., Conclusion: V Flow technique is a simple, practical, and feasible quantitative imaging approach for assessing WSS and Tur in peripheral arteries. It has the potential to be a useful tool for evaluating atherosclerotic plaques in peripheral arteries. The results provide a new quantitative foundation for future investigations into diverse arterial hemodynamic parameters., Competing Interests: Authors YgD and SL were employed by Shenzhen Mindray Bio-Medical Electronics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Liu, Dong, Hong, Chen, Du, Li, Xu, Gao and Dong.)

Data sharing is very important for medical researchers to do research on certain diseases in cloud-assisted electronic medical systems. Nonetheless, there are large amounts of duplicate data in shared electronic medical records, which incurs redundant storage. In addition, data sharing of electronic medical records might expose the sensitive information of patients. In order to address above problems, we propose a secure data sharing scheme with data deduplication and sensitive information hiding in cloud-assisted electronic medical systems in this paper. In order to protect the sensitive information privacy and enhance the deduplication efficiency, we replace the patient's sensitive information of electronic medical records by wildcards before encrypting the whole electronic medical records. The authorized researcher can decrypt and obtain the electronic medical records under the condition that the sensitive information of shared electronic medical records is hidden. Moreover, we clarify the diagnose information of the electronic medical records into different types according to the duplicate ratio. The authorized researchers can selectively download data according to the duplicate ratio of diagnostic information. Our proposed scheme can resist brute-force attacks and single-point-of-failure attack. The experimental results show our proposed scheme is more efficient than the existing schemes., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking., Results: We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%., Conclusions: Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis., (© 2022. The Author(s).)

It has been previously postulated that blood neurotransmitters might affect risks of neurodegenerative diseases. Here, a Mendelian Randomization (MR) study was conducted to explore whether genetically predicted concentrations of glycine, glutamate and serotonin were associated with risks of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). From three genome-wide association studies of European ancestry, single nucleotide polymorphisms strongly associated with glycine, glutamate and serotonin were selected as genetic instrumental variables. Corresponding summary statistics were also obtained from the latest genome-wide association meta-analyses of AD, PD and ALS. The inverse-variance weighted MR and multiple sensitivity analyses were performed to evaluate causal effects of genetically predicted levels of neurotransmitters on risks of neurodegenerative diseases. The statistical significance threshold was set at P < 0.0056 using the Bonferroni-correction, while 0.0056 < P < 0.05 was considered suggestive evidence for a causal association. There was a causal association of elevated blood glutamate levels with higher AD risks. The odds ratio (OR) of AD was 1.311 [95% confidence interval (CI), 1.087-1.580; P = 0.004] per one standard deviation increase in genetically predicted glutamate concentrations. There was suggestive evidence in support of a protective effect of blood serotonin on AD (OR = 0.607; 95% CI, 0.396-0.932; P = 0.022). Genetically predicted glycine levels were not associated with the risk of AD (OR = 1.145; 95% CI, 0.939-1.396; P = 0.180). Besides, MR analyses indicated no causal roles of three blood neurotransmitters in PD or ALS. In conclusion, the MR study provided evidence supporting the association of elevated blood glutamate levels with higher AD risks and the association of increased blood serotonin levels with lower AD risks. Triangulating evidence across further study designs is still warranted to elucidate the role of blood neurotransmitters in risks of neurodegenerative diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Deng, Lin, Gao, Liu and Xia.)

Background: Evidence suggests that nonalcoholic fatty liver disease (NAFLD) is associated with cardiovascular diseases (CVDs). However, the results are inconsistent, and the causality remains to be established., Objective: We aimed to investigate the potential causal relationship between NAFLD and CVDs, including arterial stiffness, coronary artery disease, heart failure, stroke, ischemic stroke and its subtypes using two-sample Mendelian randomization (MR)., Methods: Genetic instruments were used as proxies for NAFLD. Publicly available summary-level data were obtained from the UK Biobank, the CARDIoGRAMplusC4D Consortium, the MEGASTROKE Consortium, and other consortia. Six complementary MR methods were performed, including inverse variance weighted method (IVW), MR-Egger, weighted median, weighted mode, MR-PRESSO, and MR-RAPS., Results: NAFLD was significantly associated with arterial stiffness (β = 0.04 [95%CI, 0.02-0.06], P = 5.53E-04). Moreover, the results remained consistent and robust in the sensitivity analysis. As for heart failure, the IVW method suggested that NAFLD was significantly associated with heart failure (OR = 1.08, 95%CI: 1.02-1.14, P = 0.005) in the absence of pleiotropy. However, there were no significant associations of NAFLD with coronary artery disease, stroke, ischemic stroke, or any ischemic stroke subtype., Conclusion: The MR study supported the causal effect of NAFLD on arterial stiffness. However, the study did not provide enough evidence suggesting the causal associations of NAFLD with heart failure, coronary artery disease, and any stroke subtypes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cholesterol is a vital building block for animal cell membranes and participates in the synthesis of various hormones. Accurate quantitation of cholesterol in food is crucial for healthy diets. Here, we describe an enzyme-assisted reactive matrix-assisted laser desorption/ionization mass spectrometry (ReMALDI-MS) assay for the quantification of cholesterol in food. First, cholesterol was converted to 4-cholesten-3-one using the cholesterol oxidase, and then reacted with a reactive matrix, 4-hydrazinoquinazoline (4-HQ), to form a hydrazone bond. Utilizing 4-HQ significantly improved the ionization efficiency of cholesterol, which possesses poor ionization efficiency in MALDI-MS, and no additional tedious derivatization/purification steps were needed. Thus, the proposed assay was successfully used for the quantification of cholesterol in bovine milk and cream. The standard recovery tests show a recovery range of 95.3-103.0% with a relative standard deviation of 0.3-3.1%. Therefore, the proposed enzyme-assisted ReMALDI-MS assay has great potential for quantification of cholesterol in other foods., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Differentiating methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA and MSSA) is crucial for clinical diagnosis and anti-microbial treatment. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is an efficient tool for identifying pathogenic microorganisms at the bacterial species level. Here, we found that MRSA and MSSA can be differentiated by MALDI-TOF MS by employing (E)-propylα-cyano-4-hydroxyl cinnamylate (CHCA-C3) as the matrix, which shows great performance for proteins/peptides, especially hydrophobic proteins. The results show that the mass spectra profile of standard MRSA (ATCC 43300) is significantly different from the profiles of standard MSSA strains (ATCC 25923 and 29213) when using CHCA-C3 as the matrix compared to traditional matrix. The mass profiles had great reproducibility and were scarcely influenced by the growth medium. Due to the enhanced discrimination ability of CHCA-C3, we collected the mass spectra of 62 clinical S. aureus strains and selected four representative peaks for principal component analysis, which showed great differentiation. Our results suggest that employing a suitable matrix could enhance the discrimination ability of antibiotic-resistant bacteria by MALDI-TOF MS., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The 2019 coronavirus disease pandemic (COVID-19) poses an enormous threat to public health worldwide, and the ensuing management of social isolation has greatly decreased opportunities for physical activity (PA) and increased opportunities for leisure sedentary behaviors (LSB). Given that both PA and LSB have been established as major influencing factors for obesity, diabetes and cardiometabolic syndrome, whether PA/LSB in turn affects the susceptibility to COVID-19 by disrupting metabolic homeostasis remains to be explored. In this study, we aimed to systematically evaluate the causal relationship between PA/LSB and COVID-19 susceptibility, hospitalization and severity using a Mendelian randomization study., Methods: Data were obtained from a large-scale PA dataset (N = 377,000), LSB dataset (N = 422,218) and COVID-19 Host Genetics Initiative (N = 2,586,691). The causal effects were estimated with inverse variance weighted, MR-Egger, weighted median and MR-PRESSO. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. Risk factor analyses were further conducted to investigate the potential mediators., Results: Genetically predicted accelerometer-assessed PA decreased the risk for COVID-19 hospitalization (OR = 0.93, 95% CI 0.88-0.97; P = 0.002), while leisure television watching significantly increased the risk of COVID-19 hospitalization (OR = 1.55, 95% CI 1.29-1.88; P = 4.68 × 10 -6 ) and disease severity (OR = 1.85, 95% CI 1.33-2.56; P = 0.0002) after Bonferroni correction. No causal effects of self-reported moderate to vigorous physical activity (MVPA), accelerometer fraction of accelerations > 425 milligravities, computer use or driving on COVID-19 progression were observed. Risk factor analyses indicated that the above causal associations might be mediated by several metabolic risk factors, including smoking, high body mass index, elevated serum triglyceride levels, insulin resistance and the occurrence of type 2 diabetes., Conclusion: Our findings supported a causal effect of accelerometer-assessed PA on the reduced risk of COVID-19 hospitalization as well as television watching on the increased risk of COVID-19 hospitalization and severity, which was potentially mediated by smoking, obesity and type 2 diabetes-related phenotypes. Particular attention should be given to reducing leisure sedentary behaviors and encouraging proper exercise during isolation and quarantine for COVID-19., (© 2022. The Author(s).)

Objectives: This study aimed to estimate the association between overweight and type 2 diabetes mellitus (T2DM) in twins, and further to explore whether genetic and early-life environmental factors account for this association., Methods: This study included 31,197 twin individuals from the Chinese National Twin Registry (CNTR). Generalized estimating equation (GEE) models were applied for unmatched case-control analysis. Conditional logistic regressions were used in co-twin matched case-control analysis. Logistic regressions were fitted to examine the differences in odds ratios (ORs) from the GEE models and conditional logistic regressions. Bivariate genetic model was used to explore the genetic and environmental correlation between body mass index (BMI) and T2DM., Results: In the GEE model, overweight was associated with a higher T2DM risk (OR=2.71, 95% confidence interval (CI): 1.96∼3.73), compared with participants with normal BMI. In the multi-adjusted conditional logistic regression, the association was still significant (OR=2.60, 95% CI: 1.15∼5.87). The ORs from the unmatched and matched analyses were different (P = 0.042). Particularly, overweight could increase T2DM risk in monozygotic (MZ) twins, and the difference in ORs between the unmatched and matched designs was significant (P = 0.014). After controlling for age and sex, the positive BMI-T2DM association was partly due to a significant genetic correlation (rA= 0.31, 95% CI: 0.20∼0.41)., Conclusions: Our findings suggest that genetics and early-life environments might account for the observed overweight-T2DM association. Genetic correlation between BMI and T2DM further provides evidence for the influence of overlap genes on their association., Competing Interests: Declaration of competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

This population-based observational, cross-sectional, and descriptive survey was to investigate the relationship of increased face mask usage in the coronavirus disease (COVID-19) era with mask-associated dry eye (MADE). Participants aged 6-79 years old with formal school education were selected. All participants finished the 19-item questionnaire online, distributed through different social media platforms. From 6925 participants who submitted eligible questionnaires, MADE was reported in 547 participants, which included 419 participants who developed new dry eye symptoms after wearing face masks and 128 participants whose pre-existing dry eye symptoms worsened with mask wearing. Longer time of face mask wearing, nonstandard wearing of face masks, reduced outdoor time, decreased daily reading time, shortened visual display terminals time, and dry environment were positively associated with MADE. There were significant associations between perceived MADE and age, female sex, education, use of glasses and contact lenses, and pre-existing dry eye. MADE was more common in adults aged > 20 years than those aged ≤ 20 years or juveniles. MADE incidence increased. Standard wearing of face masks was suggested as a protective factor for MADE. Awareness about the possible risk of MADE should also be created and the clinical dry eye signs should be verified.Clinical trial registration number: NCT04744805., (© 2022. The Author(s).)

Objective: This study aimed to examine the association of socioeconomic status with obesity., Methods: A total of 39,262 twin individuals were included from the Chinese National Twin Registry (CNTR). Generalized estimating equation models for unmatched twin individual analyses and conditional logistic regression for the co-twin matched design were used. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) was used to explore the evidence of a causal relationship., Results: In general estimating equation models, high education level and income were associated with lower risk of obesity (odds ratio [OR] = 0.74 [95% CI: 0.65 to 0.84] and 0.86 [95% CI: 0.77 to 0.96]). In conditional logistic regression analysis, the association with education was significant (OR = 0.50 [95% CI: 0.34 to 0.74]) but the association with income was insignificant (OR = 0.74 [95% CI: 0.48 to 1.15]). From the ICE FALCON analysis, a twin's obesity was associated with the co-twin's education and income. After adjusting for the twin's own education, the association disappeared ( β co - twin '  = -0.10 [95% CI: -0.26 to 0.07]), whereas the twin's obesity was still associated with the co-twin's income but attenuated toward the null ( β co - twin '  = -0.21 [95% CI: -0.36 to -0.06])., Conclusions: Socioeconomic status is negatively associated with obesity. Education may have a causal effect on obesity, whereas the association between income and obesity is confounded by familial factors., (© 2022 The Obesity Society.)

Background: Early gestational age (GA) assessment using ultrasound is a routine and frequent examination performed in hospitals whereby clinicians manually measure the size of the gestational sac using ultrasound and calculate GA. However, the error is often substantial, and the process is laborious. To overcome these challenges, we propose a new system to assess early GA using a new end-to-end computer vision system and a new biometric measurement method based on ultrasound video., Methods: In this retrospective study, a new system was provided. B-ultrasound videos were first decomposed into two-dimensional (2D) images, and the contours of the gestational sac were extracted and drawn. The maximum length and short diameter of the gestational sac were then automatically measured and GA was calculated using the Hellman formula. Finally, through human-machine comparison, the clinicians' assessment errors were analyzed by SPSS 26., Results: In this study, 29,829 2D images of 191 B-ultrasound videos were evaluated using the new system. Clinicians usually require 15-20 min to complete assessments of GA, whereas with the new system assessments can be completed in approximately 30 s. Moreover, a human-machine comparison showed that the system helped intermediate skills clinicians improve their relative diagnostic error by 13.45% with an absolute error of 7 days. In addition, the new system was used to identify other lesions in the uterus and measure their size as a "sanity check"., Conclusions: The proposed new system is a practical, reproducible, and reliable approach for assessing early GA., Competing Interests: Conflicts of Interest: All authors completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-21-837/coif). The authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)